Chequerboard titration of cephalosporin CXA-101 (FR264205) and tazobactam versus beta-lactamase-producing Enterobacteriaceae

J Antimicrob Chemother. 2010 Sep;65(9):1972-4. doi: 10.1093/jac/dkq248. Epub 2010 Jun 30.


Background: The developmental oxyimino-cephalosporin CXA-101 (FR264205) is notable for having greater antipseudomonal activity than ceftazidime. It is active against Enterobacteriaceae too, but is compromised by extended-spectrum, AmpC and carbapenem-hydrolysing beta-lactamases. We investigated the tazobactam concentrations needed to potentiate this cephalosporin against strains with these mechanisms.

Methods: MIC chequerboards were prepared between CXA-101 and tazobactam (1-32 mg/L) using CLSI agar dilution methodology and a challenge panel of 'difficult' Enterobacteriaceae isolates.

Results: Only 20% of 59 extended-spectrum beta-lactamase (ESBL) producers were susceptible to unprotected CXA-101 at 8 mg/L (5% at 2 mg/L), but 76% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 93% at 8 + 8 mg/L. Among 20 AmpC-derepressed organisms, three of four Serratia spp. were susceptible to CXA-101 at 1-2 mg/L, but other species with the mechanism were more resistant; nevertheless, 70% were susceptible to CXA-101 + tazobactam at 8 + 4 mg/L and 95% at 8 + 8 mg/L. The six least-susceptible AmpC-derepressed isolates were all Enterobacter spp. The MICs of CXA-101 for Klebsiella oxytoca isolates hyperproducing K1 enzyme were 4 mg/L and were not significantly reduced by tazobactam: those for Klebsiella pneumoniae with KPC enzymes were >or=128 mg/L and, in four out of five cases, were not significantly reduced by tazobactam.

Conclusions: Tazobactam achieved concentration-dependent potentiation of CXA-101 versus ESBL producers and AmpC hyperproducers. If a breakpoint of 8 + 8 mg/L can be justified pharmacokinetically, CXA-101 + tazobactam should be active versus >90% of ESBL producers, AmpC hyperproducers and K1 hyperproducers. Most isolates with KPC or other carbapenemases will remain resistant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / biosynthesis
  • Cephalosporins / pharmacology*
  • Enterobacteriaceae / drug effects*
  • Enterobacteriaceae / enzymology*
  • Enzyme Inhibitors / pharmacology*
  • Microbial Sensitivity Tests
  • Penicillanic Acid / analogs & derivatives*
  • Penicillanic Acid / pharmacology
  • Tazobactam
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / biosynthesis


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Cephalosporins
  • Enzyme Inhibitors
  • beta-Lactamase Inhibitors
  • ceftolozane
  • Penicillanic Acid
  • beta-Lactamases
  • Tazobactam